One of the features of brain dysfunction is schizophrenia (SCZ) is a functional and structural abnormality in prefrontal-hippocampal circuitry, reflected in neurocognitive deficits in attention, working and declarative memory, and executive functions. Clues to the cause of these and other brain abnormalities come from data indicating that some non-psychotic first-degree relatives of patients with SCZ manifest a similar but milder syndrome. We are proposing to test hypotheses that prefrontal-hippocampal abnormalities are part of the core vulnerability to the illness, and are specific to SCZ, in comparison to bipolar psychotic (BP) disorder. We plan to conduct a family study of the effects of genetic vulnerability and prenatal and perinatal complications (PPCs) on brain and neuropsychological abnormalities. BP is an excellent comparison group for SCZ because it shares the following features: psychosis, a complex genetic etiology, similar sex distributions, an excess of winter-spring births and PPCs. A direct comparison of relatives of BP with relatives of SCZ avoids potential confounds such as medication differences between patients, and differing effects of psychosis on outcome measures. We have a unique opportunity to address these issues by conducting a family study nested within an inter-generational, longitudinal, community cohort study of pregnancies drawn from the Providence and Boston cohorts of the National Collaborative Perinatal Project. Given the richness of this prospective sample, with which we have worked for more than a decade, we will be able to rigorously measure PPCs (using obsterical records and prenatal sera) and relate these to neurobehavioral consequences at ages 36-43. Cases and siblings will be comparable to normal controls based on age, sex, ethnicity, parental SES and study site; additionally siblings and controls will be made comparable on PPCs. We are proposing to collect structural and functional magnetic resonance images, neurocognitive tests, and blood to be banked for later DNA analysis, from 100 cases of psychosis, all of their available siblings (n=100), and SO normal controls. We hope to clarify the etiology of these abnormalities, and enable more precise identification of heritable forms of abnormal brain circuitry. Moreover, if rigorous definitions of PPCs are used, it will be possible to identify the specific types of PPCs associated with brain abnormalities, which can lead to prevention strategies.